1. Field of the Invention
This invention relates to a novel polymerizable liposome-forming lipid, a method for the production thereof, and use thereof. More particularly, this invention relates to a polymerizable liposome-forming lipid capable of forming polymerized liposomes of excellent stability and to a method for the production thereof. This invention relates further to a novel medical carrier.
2. Description of Prior Art
At various efforts are being made to encapsulate medicinal substances, enzymes, etc. in microcapsules and offer the filled microcapsules as medicines. The microcapsules filled with hemoglobin serve as artificial red cells.
The microcapsulation, in the early stage of its development, relied on the capsulation of a high molecular compound by emulsification or on the capsulation by surface polycondensation entailing the formation of a polymer (polyamide). These conventional methods, however, have posed problems such as the inclination toward induction of thrombosis and other disorders which are fatal to the adoption of microcapsulated preparations as medicines, because the polymers as the materials for capsulation are poisonous, the organic solvents inevitably used during the synthesis of such polymers and suffered to remain in the produced capsules are poisonous, and the capsules have a large particle size (several .mu.m to 1,000 .mu.m).
Incidentally, the microcapsulation of medicinal substances, enzymes, hemoglobin, etc. is mainly aimed at enabling the medicinal substances, enzymes, hemoglobin, etc. which are unstable in vivo to retain their activities for a long time and allowing their effects to last long.
For a microcapsulating material to be admitted for in vivo application or for preparation of a medicine, it is required to manifest only minimal toxicity to the living body, permit sufficient reduction in the particle diameter of capsules, and enable the capsules to enjoy ample stability in vivo.
The liposomes which are fine spherical compartments formed in water by oriented aggregation of various phospholipids, the main components for living membranes, satisfies these conditions fairly well. The potentiality of utility of the liposome as a microcapsulating material, therefore, has come to arrest growing attention.
The liposomes which use natural phospholipids as they are, however, have a short life and manifest poor stability in its interaction particularly with living cells. In the field of drug deliveries which are utilized as carriers for supporting medicines within the liposomes, and of model studies on recognition or interaction between cells, therefore, numerous studies are now under way in search of stable liposomes. At present, the most efficient approach to the stabilization resides in polymerization of the existing liposomes.
The polymerization of the liposomes are aimed at stabilizing the lipid bilayer membranes and consequently the structure of vesicle structure through the medium of the covalent bond of lipid molecules. This stabilization is preponderantly attained by a procedure which comprises incorporating a polymerizable functional group into the lipid molecule thereby preparing monomeric liposomes and thereafter causing polymerization of the lipid within the membrane of the liposomes. A typical version of this method, as described in J. Am. Chem. Soc., 106, 1627-1633 (1984), for example, involves first synthesizing an unsaturated fatty acid and then esterifying the unsaturated fatty acid with the hydrolyzate of a phospholipid thereby incorporating a polymerizable reactive group into the phospholipid. In accordance with this method, however, the synthesis of the unsaturated fatty acid calls for a great deal of time and labor and the isolation of the product of synthesis turns out to be an extremely complicated work, and the polymerizable phospholipid is obtained as the final product in a yield of only several percent as reported in the literature. The inventors, by faithfully repeating the experiment reported, obtained the phospholipid in a yield about one tenth of the yield reported in the literature.
Attempts are being made also to utilize liposomes as the material for the artificial red cells obtainable by microcapsulation of hemoglobin. It is expected that leakage of hemoglobin into blood plasma which is a serious problem to the liposome formed solely of natural phospholipid will be effectively curbed by utilizing polymerized liposomes using polymerizable phospholipids.
A few problems, however, stand on the way to successful utility of the polymeric liposomes as a material for the artificial blood. Firstly, since the polymerizable phospholipids are synthesized purely organic chemically through a multiplicity of serial reactions on the basis of extremely elaborate molecular design, it cannot be easily synthesized in a large volume from the practical point of view and cannot help being extremely expensive. Secondly, the method of polymerization for producing the polymeric liposomes have much to be desired. Generally, the reaction for polymerization of the polymerizable phospholipids is carried out by using a radical polymerization initiator or ultraviolet light. The method using the initiator, however, is undesirable where the product of polymerization is intended for in vivo application because the method generally requires application of heat and also because the initiator persists in the produced liposomes. The method resorting to ultraviolet light has the disadvantage that the hemoglobin in the capsules is susceptible to denaturation because the conventional phospholipids are not sufficiently polymerizable and are required to be amply irradiated.
An object of this invention, therefore, is to provide a novel polymerizable liposome-forming lipid and a method for the production of the lipid.
Another object of this invention is to provide excellently stable polymeric liposomes and a method for the production of the lipid.
Yet another object of this invention is to provide polymeric liposome-forming lipids such that the monomeric liposome formed of the lipid is easily polymerized under mild conditions and a method for the production of the lipid.
Still another object of this invention is to provide a novel medical carrier.
A further object of this invention is to provide a medical carrier made of excellently stable polymeric liposome-forming lipids.
Another object of this invention is to provide a medical carrier suffering from only nominal leakage of a carried substance.
Still another object of this invention is to provide a medical carrier useful for microcapsulation of hemoglobin, for example.